Cholinesterase is an enzyme that is widely distributed in a living body and hydrolyzes choline esters such as acetylcholine.
As the cholinesterase, there have heretofore been known two kinds of cholinesterase, i.e., specific (true) cholinesterase that exists in a brain, nervous tissue such as an autonomic nerve and a neuromuscules junction, an erythrocyte membrane, and the like, and nonspecific (pseudo) cholinesterase that exists in a serum, the pancreas and the like.
These kinds of cholinesterase are inhibited not only by cholinesterase inhibitors such as neostigmine but also by various medicines, in particular, carcinostatics, organic phosphorus agents and the like. The reduction in cholinesterase activities is considered to form the main cause that the side effects of various medicines are manifested. It is further known that cholinesterase activities are reduced even by hepatopathy.
For example, irinotecan hydrochloride, which is in use as a carcinostatic, is recognized to manifest grave diarrhea as a side effect. The diarrhea is manifested on the basis of a cholinesterase-inhibiting action due to administration of irinotecan hydrochloride.
Besides, 1,2,3,4-tetrahydro-9-acridinamine (hereinafter referred to as "THA") of a cholinesterase inhibitor, which has been used as a remedy for an Alzheimer's disease in recent years, inhibits not only central cholinesterase but also peripheral cholinesterase and is hence recognized to manifest side effects such as sialorrhea, nausea, diarrhea sweating and hepatopathy.
On the other hand, when the central cholinesterase is activated, the amount of acetylcholine in a brain is decreased, so that the diseased condition of a patient suffering from a Parkinson disease, senile dementia or the like is considered to be worsened.
Accordingly, it is necessary to administer an agent, which can selectively activate the peripheral cholinesterase, for the side effects of various medicines manifested on the basis of their cholinesterase-inhibiting action. However, any agent which can selectively activate central or peripheral cholinesterase has not been yet present, and there is hence a demand for development of a novel cholinesterase activator having such a selectively activating action.
The present inventors have carried out an extensive investigation with a view toward solving the above problem. As a result, it has been surprisingly found that a compound represented by the general formula (I) has a strongly activating action on cholinesterase, and such a activating action selectively works on peripheral cholinesterase, thus leading to completion of the present invention.